Pyrazoline Nucleus Research Articles

Synthesis, molecular docking and pharmacological evaluations of novel naphthalene-pyrazoline hybrids as new orally active anti-inflammatory agents

The pyrazoline nucleus is widely present in diverse compounds as it serves as a valuable template for the discovery of new class of bioactive compounds. Various substituted 2-pyrazolines exhibit a spectrum of pharmacological activities, including antimicrobial, anti-inflammatory, analgesic, and antitumor properties. In view of this, we have synthesized a novel class of naphthalene-pyrazoline hybrids (PY1-PY20). All the synthesized hybrids were thoroughly characterized by means of standard spectroscopic techniques and tested for their in-vivo anti-inflammatory activity. Most of the compounds exhibited significant anti-inflammatory activity and in particular the compounds bearing electron withdrawing groups had potential in vivo activity. Further, in-silico molecular docking studies were carried out using the ‘Molegro Virtual Docker’ as a docking tool against the target proteins such as COX-1 (PDB ID: 1EQH) and COX-2 (PDB ID: 1PXX). The results revealed that the majority of pyrazolines form hydrogen interactions with key residues (Ser 530, Tyr 385, Tyr 355, Arg 120, Ser 353, Arg 83) in the active binding sites of COX-1 (1EQH) and COX-2 (1PXX). Notably, interactions with residues Tyr 355, Arg 120, Ser 530 for COX-1, and Tyr 355, Arg 120, Gln 192, Leu 352, Ser 353, His 90, Tyr 38, Ser 530, and Tyr 385 for COX-2 are crucial for the reported anti-inflammatory activity of diverse compounds. Ligand-protein inverse molecular docking studies highlight specific hydrogen bond interactions, with PY-8, PY-11, PY-15, and PY-17 showing significant interactions. The study was able to identify potential anti-inflammatory naphthalene-pyrazoline derivatives.

In vitro and in silico studies on novel N-substituted-3,5-diaryl-pyrazoline derivatives as COX-2 inhibitors and anti-inflammatory agents

The presence of a reactive α,β-unsaturated keto group along with substituted aryl ring improves biological profile of pyrazoline nucleus. Considering this fact a study was planned to synthesize novel pyrazoline derivatives incorporated with chalcone backbone and their evaluation as COX-2 inhibitors and anti-inflammatory agents. Bovine serum albumin denaturation assay was used to measure in vitro anti-inflammatory activity. Molecular docking study was performed using Schrödinger-Maestro 9.0 molecular docking software and cyclooxygenase-2 (COX-II) receptor PDB ID: 4-COX. Some of the synthesized compounds showed remarkable anti-inflammatory potential. The compound (E)-3-(4-hydroxyphenyl)-1-(3-(4-hydroxyphenyl)-5-phenyl-4,5-dihydropyrazol-1-yl)prop-2-en-1-one 6d was found to be the most potent anti-inflammatory agents with 69.88% inhibition of protein denaturation. The outcome of docking study also supported results of in vitro anti-inflammatory activity and docking score for compound 6d was found to be –6.70379 which was comparable to the co-crystallized ligand. The results reveal that the synthesized compound can serve as potential lead for the development of novel anti-inflammatory agents.

Density functional modeling, and molecular docking with SARS-CoV-2 spike protein (Wuhan) and omicron S protein (variant) studies of new heterocyclic compounds including a pyrazoline nucleus

Nowadays, different vaccines and antiviral drugs have been developed and their effectiveness has been proven against SARS-CoV-2. Pyrazoline derivatives are biologically active molecules and exhibit broad-spectrum biological activity properties. In this scope, four new molecules (4a–d) including a pyrazoline core were synthesized in order to predict their antiviral properties theoretically. Compounds 4a–d were purified by the crystallization method. The structures of 4a–d were completely characterized by NMR, IR, and elemental analysis. The molecular structures of the compounds in the ground state have been optimized using density functional theory with the B3LYP/6-31++G(d,p) level. The quantum chemical parameters were predicted by density functional theory calculations. Moreover, the molecular docking studies of 4a–d with SARS-CoV-2 Spike protein (Wuhan) and omicron S protein (variant) were presented to investigate and predict potential interactions. The binding sites, binding types and energies, bond distances of the non-covalent interactions and calculated inhibition constants (calc. Ki) as a consequence of molecular docking for 4a–d were presented in this study. Furthermore, the stability of the protein-4a complex obtained from the docking was investigated through molecular dynamics simulation. Communicated by Ramaswamy H. Sarma

Design, Synthesis and Pharmacological Evaluation of Novel Benzimidazole Derivatives as Anticancer Agents

Background: Cancer is undoubtedly a major challenge of modern era and is the second leading cause of death in the world. Lung cancer is the second most common cancer and the leading cause of cancer death among men and women. Non-Small Cell Lung Cancer (NSCLC) accounts for 84% of all lung cancer diagnosed. Benzimidazoles are important heterocyclic compounds possessing a variety of biological activities such as anticancer, antioxidant, anti-inflammatory, and analgesic, anti-viral, anti-bacterial, anti-fungal and hypoglycemic activities. Pyrazolines reported antitumor, immunosuppressive, antibacterial and anti tubercular agents. Biological activities of the benzimidazole derivatives depend on the functional group attached to the benzimidazole moiety. Objective: The present research focused on incorporating pyrazoline nucleus into benzimidazole nucleus to form a potent anticancer agent targeting lung cancer therapy. Method: The in silico novel pyrazoline substituted benzimidazole derivatives were designed. Docking was performed to know the binding interactions of the newer agents with the enzymes. The compounds were found to be active in docking studies synthesized and tested for anticancer activity. In vitro screening of the selected derivatives for anticancer activity by MTT assay method showed very good results. Cytotoxicity of compounds BZ1, BZ2, BZ10 and BZ16 studied against fibrosarcoma and lung cancer cell line. Results: The compound BZ1 showed highest activity against fibrosarcoma and lung cancer cell line. Conclusion: Further studies on these compounds to prove it as a lead compound in cancer therapy should be conducted.

Synthesis of 1, 3, 5-Trisubstituted Pyrazoline Nucleus Containing Compounds and Screening for Anti-Inflammatory Activity

In this study, a novel series of heterocyclic compounds containing pyrazoline nucleus has been synthesized. The compounds were synthesized in two steps. Chalcone was synthesized in the first step by Claisen-Schmidt reaction, using 1-acetylnaphthalene and p-nitrobenzaldehyde as reactants. In the second step, the chalcone was cyclized in an acidic medium with some hydrazine derivatives to form pyrazolines. All the compounds were characterized by physical, chromatographic, spectroscopic, and elemental analysis and evaluated in vitro for antimicrobial activity against nine microorganisms by cup plate method. The minimum inhibitory concentration of all the compounds was determined by tube dilution method. All the compounds exhibited higher antibacterial activity as compared to the antifungal activity. Compound 5g (3-Naphthalen-1-yl-1-(2-nitro-phenyl)-5-(4-nitro-phenyl)-4, 5-dihydro-1H-pyrazole)exhibited maximum antibacterial and antifungal activity and may be designated as the most potent member of the series, with 2-nitrophenyl group at N-1 position of the 2-pyrazoline ring.

Synthesis and biological evaluation of new derivatives of thieno-thiazole and dihydrothiazolo-thiazole scaffolds integrated with a pyrazoline nucleus as anticancer and multi-targeting kinase inhibitors.

Deregulation of various protein kinases is considered as one of the important factors resulting in cancer development and metastasis, thus multi-targeting the kinase family is one of the most important strategies in current cancer therapy. This context represents the design and synthesis of two sets of derivatives bearing a pyrazoline-3-one ring conjugated either with a thieno[3,2-d]thiazole or with a dihydrothiazolo[4,5-d]thiazole scaffold via an NH linker, 3a–d and 5a–d respectively, using the pyrazolinone–thiazolinone derivative 1 as a key precursor. All the newly synthesized compounds were assessed in vitro for their anticancer activity against two cancer cell lines (MCF-7 and HepG-2). The safety profile of the most active cytotoxic candidates 1 and 3c was further examined against the normal cell line WI-38. The compounds 1 and 3c were further evaluated as multi-targeting kinase inhibitors against EGFR, VEGFR-2 and BRAFV600E, exhibiting promising suppression impact. Additionally, the latter compounds were investigated for their impact on cell cycle and apoptosis induction potential in the MCF-7 cell line. Moreover, the antimicrobial activity of all the new analogues was evaluated against a panel of Gram-positive and Gram-negative bacteria, yeast and fungi in comparison to streptomycin and amphotericin-B as reference drugs. Interestingly, both 1 and 3c showed the most promising microbial inhibitory effect. Molecular docking studies showed promising binding patterns of the compounds 1 and 3c with the prospective targets, EGFR, VEGFR-2 and BRAFV600E. Finally, additional toxicity studies were performed for the new derivatives which showed their good drug-like properties and low toxicity risks in humans.

Design, Synthesis, and In Vitro Evaluation of Novel Indolyl DiHydropyrazole Derivatives as Potential Anticancer Agents.

Indoles derived from both natural sources or artificial synthetic methods have been known to interact with aryl hydrocarbon receptors (AhR), and exhibit anticancer activity. In light of these attractive properties, a series of hybrid molecules with structural features of indoles, i.e., those bearing a pyrazoline nucleus, were evaluated for their enhanced anticancer activity. The designed molecules were subjected to molecular docking in order to screen for potential AhR interacting compounds, and the identified indolyl dihydropyrazole derivatives were synthesized. The synthesized compounds were characterized, and their cytotoxicity was evaluated against four human cancer cell lines using the MTT assay. Based on the Glide g-score, H-bonding interactions and bonding energy of 20 candidate molecules were selected for further analysis from the 64 initially designed molecules. These candidate molecules have shown promising anti-proliferative activity against the cell lines tested. Among these candidate molecules, the compounds with hydroxy phenyl substitution on the pyrazoline ring have shown potent activity across all the tested cell lines. The designed scaffold was proven effective for screening potential candidate molecules with anticancer properties, and may be further optimized structurally for yielding the ideal anti-tumorigenic compound for the treatment of various cancers.

Design, Synthesis, Characterization and In Silico Molecular Docking Studies and In Vivo Anti-inflammatory Activity of Pyrazoline Clubbed Thiazolinone Derivatives

The pyrazolines give the reactions of aliphatic derivatives, resembling unsaturated compounds in their behavior towards permanganate and nascent hydrogen. This nucleus has been associated with various biological activities, including inflammatory action. Thiazolinone is a heterocyclic compound that contains both sulfur and nitrogen atom with a carbonyl group in their structure. Thiazolinone and their derivatives have attracted continuing interest because of their various biological activities, such as anti-inflammatory, antimicrobial, anti-proliferative, antiviral, anticonvulsant, etc. The aim of the research was to club pyrazoline nucleus with thiazolinone in order to have a significant anti-inflammatory activity. The synthesized compounds were chemically characterized for the establishment of their chemical structures and to evaluate it as an anti-inflammatory agent. In the present work, eight derivatives of substituted pyrazoline (PT1-PT8) were synthesized by a threestep reaction. The compounds were subjected to spectral analysis by Infrared, Mass, and Nuclear magnetic resonance spectroscopy and elemental analysis data. All the synthesized derivatives were evaluated for their in vivo anti-inflammatory activity. The synthesized derivatives were evaluated for their affinity towards target COX-1 and COX-2, using indomethacin as the reference compound molecular docking visualization through AutoDock Vina. Compounds PT-1, PT-3, PT-4, and PT-8 exhibited significant anti-inflammatory activity at 3rd hour, being 50.7%, 54.3%, 52.3%, and 57%, respectively, closer to that of the standard drug indomethacin (61.9%). From selected anti-inflammatory targets, the synthesized derivatives exhibited better interaction with COX-1 and COX-2 receptor, where indomethacin showed a docking score of -6.5 kJ/mol, compound PT-1 exhibited the highest docking score of -9.1 kJ/mol for COX-1 and compound PT-8 had a docking score of 9.4 kJ/mol for COX-2. It was concluded that synthesized derivatives have more interaction with COX-2 receptors in comparison to the COX-1 receptors because the docking score with COX-2 receptors was very good. It is concluded that the synthesized derivatives (PT-1 to PT-8) are potent COX-2 inhibitors.

Synthesis and QSAR Studies of Novel Pyrazoline Derivatives as Antiproliferative Agent

Abstract: Background: Regardless of recent advances in the biological processes leading to the development of cancer, there is still a need for new and effective agents to help bring this disease under control. The revelation of the anticancer properties of pyrazoline makes this scaffold remarkable for research and development as an anticancer. Methods: A series of synthetic chalcones and pyrazoline derivatives were synthesized, characterized IR, 1H NMR and mass spectral analysis and evaluated for their Anticancer activity on MCF-7 cell line through SRB assay. A QSAR study was performed on thirtyfive compounds of known series having pyrazoline nucleus using Accelrys Discovery Studio Vs 2.1.0.8130. Results: We found that significant inhibitory activity among all the synthesized compound 1B showing better anticancer activity having IC50 value 0.010 μM as compared to standard drug letrozole. So predicted molecules from the QSAR study show significant activity. Conclusion: We would conclude that compound 1B might serve as a potential antiproliferative agent. Key words: Pyrazoline, QSAR, SRB assay, MCF-7, Antiproliferative activity.

Synthesis of Hydroxybenzofuranyl-pyrazolyl and Hydroxyphenyl-pyrazolyl Chalcones and Their Corresponding Pyrazoline Derivatives as COX Inhibitors, Anti-inflammatory and Gastroprotective Agents.

Five new series of hydroxybenzofuranyl-pyrazolyl chalcones 3a,b, hydroxyphenyl-pyrazolyl chalcones 6a-c and their corresponding pyrazolylpyrazolines 4a, d, 7a-c and 8a-f have been synthesized and evaluated for their in vitro cyclooxygenase (COX)-1 and COX-2 inhibitory activity. All the synthesized compounds exhibited dual COX-1 and COX-2 inhibitory activity with obvious selectivity against COX-2. The pyrazolylpyrazolines 4a-d and 8a-f bearing two vicinal aryl moieties in the pyrazoline nucleus showed more selectivity towards COX-2. Within these two series, derivatives 4c, d and 8d-f bearing the benzenesulfonamide group were the most selective. Compounds 4a-d and 8a-f were further subjected to in vivo anti-inflammatory screening, ulcerogenic liability and showed good anti-inflammatory activity with no ulcerogenic effect. In addition compounds 4c and 8d as examples showed prostaglandin (PG)E2 inhibition % 44.23 and 51.4 respectively, tumor necrosis factor α (TNFα) inhibition % 33.48 and 41.41 respectively and gastroprotective effect in ethanol induced rodent gastric ulcer model. In addition, to explore the binding mode and selectivity of our compounds, 8d and celecoxib were docked into the active site of COX-1 and COX-2. It was found that compound 8d exhibited a binding pattern and interactions similar to that of celecoxib with COX-2 active site, while bitter manner of interaction than celecoxib to COX-1 active site.

Pyrazoline Hybrids as Promising Anticancer Agents: An Up-to-Date Overview.

Pyrazolines are five-membered heterocycles possessing two adjacent nitrogens. They have attracted significant attention from organic and medicinal chemists due to their potent biological activities and the numerous possibilities for structural diversification. In the last decade, they have been intensively studied as targets for potential anticancer therapeutics, producing a steady yearly rise in the number of published research articles. Many pyrazoline derivatives have shown remarkable cytotoxic activities in the form of heterocyclic or non-heterocyclic based hybrids, such as with coumarins, triazoles, and steroids. The enormous amount of related literature in the last 5 years prompted us to collect all these published data from screening against cancer cell lines, or protein targets like EGFR and structure activity relationship studies. Therefore, in the present review, a comprehensive account of the compounds containing the pyrazoline nucleus will be provided. The chemical groups and the structural modifications responsible for the activity will be highlighted. Moreover, emphasis will be given on recent examples from the literature and on the work of research groups that have played a key role in the development of this field.

A REVIEW ON ANTI-INFLAMMATORY POTENTIAL OF SUBSTITUTED PYRAZOLINE DERIVATIVES SYNTHESISED FROM CHALCONES

The pyrazoline ring is a ubiquitous structural feature of many natural and synthetic compounds with potent anti-inflammatory activity. The creation of novel pyrazoline derivatives and examination of their chemical and biological behaviour have gained additional focus in the current decade. Pyrazolines and its fused heterocyclic derivatives tested with anti-inflammatory activity constitute a significant class of compounds for novel drug evolution. Pyrazoline nucleus when linked with different substituents like alkyl, aromatic, heterocyclic rings and many other groups at different positions on the ring shows considerable to more effective anti-inflammatory activity. This article presents a comprehensive review of the anti-inflammatory activity of some novel derivatives of pyrazoline ring.

Design, synthesis and biological evaluation of pyrazoline nucleus based homoleptic Ru(iii) compounds

Biological applications of homoleptic Ru(iii) compounds towards molecular docking, DNA-binding and DNA cleavage.

Synthesis, in silico preclinical evaluation, antidepressant potential of 5-substituted phenyl-3-(thiophen-2-yl)-4,5-dihydro-1h-pyrazole-1-carboxamides

In the context of the discovery of new potential antidepressant candidates and in the light of promising antidepressant action of pyrazoline nucleus, a new series of thiophene bearing pyrazoline carboxamides were synthesized and examined for their antidepressant effect by two behavioural models viz. Forced Swim Test (FST) and Tail Suspension Test (TST). Neurotoxicity of the compounds were accessed by rotarod test. The titled compounds were characterized by IR, 1H NMR, 13C NMR and mass and elemental analyses. The preclinical evaluation the compounds were predicted by in silico toxicity, blood-brain barrier and human oral absorption. In this series, 5-(3-nitrophenyl)-3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carboxamide (TSe) reduced immobility time 60.43 and 63.47% in both FST and TST, respectively at 10mg/kg dose level when compared to the standard imipramine. Moreover, it was observed that the compounds possessing electron-releasing groups such as dimethyl amino, methoxy and electron-withdrawing chlorine in the 4th position of aromatic rings of the scaffold showed good antidepressant activity when compared to the pyrazolines having no substituents on the phenyl rings. All the compounds in the series have passed neurotoxicity test.

Pyrazoline: A Promising Scaffold for the Inhibition of Monoamine Oxidase

In the five membered nitrogen containing heterocyclic family, pyrazoline could be recognized as a promising scaffold for the inhibition of Monoamine oxidase. Substitution at 1, 3 and 5-position of the pyrazoline nucleus displayed a significant activity towards MAO in the past 15 years. Our study identified the detailed structure activity relationship, the structural requirement for enzyme interaction and the effect of chirality on the pyrazoline nucleus towards MAO-A and MAO-B. We propose that the selectivity of pyrazoline nucleus towards MAO isoenzyme depends up on the bulkiness of the ring in the 1 and 3 position of the scaffold. The current review revealed that the derivatives of pyrazolines have proven to be versatile pharmacophores for the inhibition of MAO on the basis of existing literatures between (1998-2013).

Synthesis and evaluation of anti-tubercular activity of some novel 2-pyrazoline derivatives

Purpose: Pyrazolines and its derivatives are reported to possess a wide spectrum of biological activities. Many class of chemotherapeutic agents containing pyrazoline nucleus are in clinical use. The purpose of this present study was to examine whether the molecular modification might result in detection of new potent anti-tubercular agent. Materials and Methods: A series of 2-pyrazoline compounds (P13-P24) have synthesized by treating N-(substituted aryl)-acrylamide (C13-C24). The starting material was synthesized from substituted P-aminoacetophenone and substituted benzaldehyde. Their structure was confirmed by infrared and 1 H NMR spectral data. The synthesized compounds were screened for anti-tubercular activity by Microplate Alamar Blue Assay method. Results: Compound P 15 and P 20 have shown excellent anti-tubercular activity; compound P 16 and P 22 have shown significant activity as compared with the standard and rest of them have shown moderate to low anti-tubercular activity. Conclusion: These compounds may result in the potent anti-tubercular entity with molecular modification and manipulations.

Synthesis of 1,3,5-trisubstituted pyrazoline nucleus containing compounds and screening for antimicrobial activity

In this study, a novel series of heterocyclic compounds containing pyrazoline nucleus has been synthesized. The compounds were synthesized in two steps. Chalcone was synthesized in the first step by Claisen-Schmidt reaction, using 1-acetylnaphthalene and p-nitro benzaldehyde as reactants. In the second step, the chalcone was cyclized in an acidic medium with some hydrazine derivatives to form pyrazolines. All the compounds were characterized by physical, chromatographic, spectroscopic, and elemental analysis and evaluated in vitro for antimicrobial activity against nine microorganisms by cup-plate method. The minimum inhibitory concentration of all the compounds was determined by tube dilution method. All the compounds exhibited higher antibacterial activity as compared to the antifungal activity. Compound 5g (3-Naphthalen-1-yl-1-(2-nitro-phenyl)-5-(4-nitro-phenyl)-4,5-dihydro-1H-pyrazole) exhibited maximum antibacterial and antifungal activity and may be designated as the most potent member of the series, with 2-nitrophenyl group at N-1 position of the 2-pyrazoline ring.

Synthesis and biological evaluation of a new class of acyl derivatives of 3-amino-1-phenyl-4,5-dihydro-1 H-pyrazol-5-one as potential dual cyclooxygenase (COX-1 and COX-2) and human lipoxygenase (5-LOX) inhibitors

A series of acyl derivatives of 3-amino-1-phenyl-4,5-dihydro-1 H-pyrazol-5-one as potential human 5-LOX and COX 1 and COX-2 inhibitors structurally related to the 1-phenyl-3-pyrazolidinone (phenidone, 1) have been synthesized and the activity against COX-1, COX-2 and human 5-LOX enzymes has been evaluated. All the derivatives showed poor activity against enzymes. These data, together with our previous studies, indicated that phenidone and related compounds are not suitable as human 5-LOX inhibitors and that pyrazoline nucleus should not be considered a good scaffold for inhibitors of human 5-LOX enzyme, suggesting the necessity to revisit the proposed mechanism of action of phenidone ( 1) in human models.

The introduction of alkylidene substituents into the 4-position of the 3,3,5,5-tetramethyl-Δ1-pyrazoline nucleus by the thioketone plus diazoalkane reaction: synthesis of tetrasubstituted episulphides and alkenes

A wide range of 4-alkylidene-3,3,5,5-tetramethyl-Δ1-pyrazolines (2), potential precursors of unsymmetrical trimethylenemethane biradicals, can be made through the reaction of thioketone (3b) with various diazo compounds (9) or the reaction of diazo compound (3e) with thioketones. In some cases, depending on the nature of the substituents X and Y, thiadiazoline and/or episulphide intermediates can be isolated but in others the alkene is obtained directly. Reaction of the thioketone (3b) with the diazo compound (3e) gives the thiadiazoline (13) which, when heated in the solid state and then treated with trimethyl phosphite gives the unusual, highly crowded olefin (12). A byproduct of the reaction of thioketone (3b) with diazodicyanomethane is the novel azomethine imine (11).

Electron‐impact induced fragmentation of substituted pyrazolone azomethine dyes

AbstractThe mass spectra of 18 substituted 1‐(p‐R2‐phyeyl)‐3‐R3‐4‐(p‐R1‐phenylimino)‐2‐pyrazolin‐5‐ones have been obtained. The major cleavages under electron bombardment take place in the pyrazoline nucleus, producing four major fragment ions whose abundance is related primarily to the electronic properties of R1. These ions appear to be produced from the molecular ion via an intermediate formed by the loss of CO. In most instances metastable ions are observed for the overall decomposition of the molecular ion to the four major fragment ions. A mechanism is proposed for these cleavages.